tbuckley/cabot-search huggingface dataset:
OTHR-29. Exploring delays in diagnosis for children with brain and spinal cord tumors: a neuro-oncologist, epidemiologist and national nonprofit establish a consortium to discover the nature and extent of the problem in the United States
Authors: Kathy Riley, Scott Coven, Jennifer Cullen
Journal: Neuro-Oncology (2022)

Abstract Childhood brain and spinal cord tumors are the second most common pediatric cancer and the leading cause of disease-related mortality among children between one and nineteen years of age (Johnson &amp; Cullen, 2014). To date, literature fails to acknowledge the perceived delay in diagnosis from a caregivers’ and providers’ perspective as it relates to disparities of care for a child with a brain or spinal cord tumor. Delay in diagnosis is a term used widely to define the time interval from onset of symptoms to confirmed diagnosis (Mullen, Barr &amp; Franco, 2021). Our experience in caring for children with CNS tumors has demonstrated a disconnect in perception of delay in diagnosis between caregivers and providers. Furthermore, to our knowledge, there is no standardized data collection tool to assess delays in diagnosis and to enable the exploration of their relationship to the patient journey from time of diagnosis through long-term outcomes of patients with brain and spinal cord tumors. Timing of diagnosis of a brain or spinal cord tumor in a pediatric patient may be a predictor of clinical outcomes (Wilne, Dineen, Dommett, Chu &amp; Walker, 2013). Additionally, the length of time from symptom onset to diagnosis may exacerbate caregiver distress which, in turn, impacts clinical outcomes. Associated social determinants of health, perceptions of credibility (e.g., not being believed about symptoms), and negative interactions with health care providers may contribute to inequalities of healthcare related to delays in diagnosis. This presentation will explore themes and key factors contributing to delays in pediatric brain and spinal cord tumor diagnoses developed through the work of our consortium. The goal of our work is to develop metrics and survey items that will be used to quantify sources of delays to improve our understanding and promote greater timeliness in diagnoses (Scott, Walter, Webster, Sutton, &amp;Emery, 2013).
Detection of Prions in a Cadaver for Anatomical Practice
Authors: Takehiro Nakagaki, Miho Kaneko, Katsuya Satoh, Kiyohito Murai, Kazunobu Saiki, Gen Matsumoto, Keiko Ogami-Takamura, Kazuya Ikematsu, Akio Akagi, Yasushi Iwasaki, Toshiyuki Tsurumoto, Noriyuki Nishida
Journal: New England Journal of Medicine (2022)
Investigation of transcriptional changes underlying calcification of aortic valve
Authors: D Semenova, A Zabirnyk, A Lobov, J Vaage, A Malashicheva
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The Russian Science Foundation Introduction Aortic valve stenosis due to calcification of valve cusps is the most common valve disease in the world today. The main feature of this condition is a progressive mineralization of valve tissue. The mechanisms underlying this process is still unknown, but in recent years it has become clear that pathological mineralization of heart and blood vessels has some similarities with the physiological process of bone formation. It has been suggested that interstitial cells (VICs) are the main functional units in the valve that undergo calcification. However, the early initiating mechanisms that trigger osteogenic transformation of cells remain unclear. Purpose The aim of the present study was to elucidate the most responsive time point of osteogenic differentiation induction and to identify the main osteogenic markers that mediate pathological calcification in human aortic valve. Methods VICs were obtained from patients with aortic valve calcification and from healthy aortic valves. The effectiveness of cell cultures osteogenic differentiation was estimated by Alizarin Red staining. Investigation of gene expression changes upon osteogenic differentiation was performed by qPCR and RNA sequencing. Results We found that 48 hours after the induction of osteogenic differentiation is the most relevant time point to identify the early regulators of osteogenic transformation of the cells. That is the time when the most intensive response from osteogenic markers takes place – BGLAP, OPG, OGN, RUNX2 – in comparison to 24, 72 and 96 hours of differentiation in both patient’s and healthy cells. We found out that induction of osteogenic differentiation on early stages initiates transcriptional program that serve to induce the next molecular events which recruit phenotype-specific osteogenes. We revealed that 558 and 232 genes which were up and down regulated during differentiation were the same for healthy and patient’s cells. However, there was a number of genes which was specific for either patient’s or healthy cells. Conclusions We presume that a great amount of the main molecular participants of osteogenic differentiation is shared between different types of cells which are prone to differentiation. However, we perform the results about specificity and difference between the mechanisms of osteogenic differentiation of patient’s and healthy cells.
Utilizing Natural Language Processing (NLP) to identify breast cancer associated-lung metastases from pathology reports to delineate characteristics and challenges of this common site of breast cancer recurrence.
Authors: José Carlos Valentín López, Alice Y. Ho, Beverly Moy, Steven J. Isakoff, Dejan Juric, Leif W. Ellisen, Jeffrey M. Peppercorn, Aditya Bardia, Kevin S. Hughes, Neelima Vidula
Journal: Journal of Clinical Oncology (2022)

e13592 Background: NLP (artificial intelligence) can automate the identification of records in large datasets. The purpose of this study was to evaluate the feasibility of NLP to identify breast cancer-associated lung metastases to understand clinical characteristics and challenges posed by this common site of breast cancer recurrence. Methods: Patients with pathologically confirmed breast cancer associated-lung metastases seen at a large academic center between 3/2012-5/2019 were identified using NLP of institutional pathology reports, with an IRB approved protocol. Chart review was performed to confirm breast cancer associated-lung metastases and determine clinical and pathological features. Results: Using NLP, 32 patients with pathology reports denoting breast cancer associated-lung metastases were identified, with pathologic confirmation of lung biopsy tissue in the majority of cases (24), and pleural fluid specimens (8) on the remainder. Ten of 32 (31%) were HR+/HER2-, 3/32 (9.3%) HER2+, and 19/32 (59%) TNBC. The majority were invasive ductal carcinoma (21/26) with the remainder invasive lobular carcinoma (2/26) or mixed histology (3/26). Median age at lung metastasis diagnosis was 62 years (range 31-88). The median time to development of lung metastasis following primary breast cancer was 5.6 years (range 0-24.8 years). Fifty six percent of lung metastases were detected on imaging and 44% by symptoms including dyspnea, cough, or pain. Tumor tissue genotyping results on the lung metastases were available for 8 patients showing PI3KCA (5), TP53 (3), SMARCA4 (2), ERBB2 (1), FGFR3 (1), ATM (1), CDK4 (1), MYC (1), and ESR1 (1). Treatment after diagnosis of lung metastases included hormone therapy (61%), chemotherapy (84%), lung irradiation (26%), and surgical resection of lung metastases (6%). Lung metastases were associated with considerable morbidity including pleural effusion (15%), dyspnea (6%), pneumothorax (3%), hemothorax (3%), and atelectasis (3%). Patients diagnosed with lung metastases had brain (32%), bone (35%), renal (6%), skin (3%) and adrenal (3%) metastases during disease course. Conclusions: NLP can help identify organ specific metastases from pathology reports, such as breast cancer associated-lung metastases, which can then facilitate observational, translational, and clinical research to characterize and address challenges posed by this common site of breast cancer recurrence. This cohort of patients highlights the morbidity of breast cancer associated-lung metastases and potential role of NLP for disease characterization and clinical research. (Support from ASCO Medical Student Rotation for Underrepresented Populations Award.)
Eight-yr experience of robotic IVC thrombectomy: surgical technique, perioperative and oncologic outcomes
Authors: L. Misuraca, U. Anceschi, G. Tuderti, R. Mastroianni, M. Ferriero, A. Brassetti, A.M. Bove, S. Guaglianone, M. Desai, I.S. Gill, M. Gallucci, G. Simone
Journal: European Urology (2022)
Single-cell profiling of human heart and blood in immune checkpoint inhibitor-associated myocarditis.
Authors: Steven Michael Blum, Daniel A. Zlotoff, Neal Smith, Swetha Ramesh, Isabela Kernin, Pritha Sen, Leyre Zubiri, Alice Tirard, Mazen Nasrallah, Jessica Tantivit, Jaimie Lynn Barth, Dejan Juric, Ryan J. Sullivan, Genevieve Marie Boland, Mari Mino-Kenudson, James Stone, Molly Thomas, Kerry Lynn Reynolds, Tomas G. Neilan, Alexandra-Chloé Villani
Journal: Journal of Clinical Oncology (2022)

2507 Background: Myocarditis due to immune checkpoint inhibitors (ICIs) is uncommon; however, myocarditis due to ICIs leads to severe morbidity and even death in 20-40% of cases. The molecular underpinnings of ICI-associated myocarditis are poorly understood, and there is an unmet clinical need to identify therapeutic targets and biomarkers that can aid in disease management. Methods: Heart tissue was obtained through endomyocardial biopsy or autopsy of patients receiving ICIs and was profiled with paired single-cell RNA sequencing (scRNA-seq) and T cell receptor sequencing (TCR) using the 10x Genomics Chromium system. A control dataset was constructed using scRNAseq data of heart tissue from patients receiving ICIs but without myocarditis and a published dataset from healthy patients not receiving ICIs. Peripheral blood mononuclear cells (PBMCs) were collected at the time of myocarditis diagnosis in a larger cohort of patients and analyzed with ICI-treated controls. The CITE-Seq protocol was used to measure paired scRNA-seq, TCR, and surface proteomics in PBMCs, using serial timepoints where available. Results: Heart tissue from 13 patients with myocarditis, including three fatal cases, and seven controls yielded 77,712 single cells. Blood profiling from 27 patients with ICI myocarditis and ICI-treated controls across 54 samples yielded over 230,000 cells. ICI myocarditis tissue demonstrated an increased T cell infiltrate (OR 8.94, FDR = 0.0021). Expression of multiple inflammatory pathways, most notably interferon responses, was up-regulated across multiple immune and non-immune cell types in the setting of myocarditis, providing important pathophysiological insights. T cell clones were also found to be shared between blood and heart, enabling the identification of putative pathogenic T cell subsets. Conclusions: Increased intramyocardial T cells and the activation of interferon response gene networks were seen in the setting of ICI myocarditis. These preliminary findings highlight potential pathological pathways in ICI myocarditis that could serve as biomarkers or therapeutic targets.
Frailty prevalence and impact on outcomes in patients with atrial fibrillation: A systematic review and meta-analysis of 1,187,000 patients
Authors: Marco Proietti, Giulio Francesco Romiti, Valeria Raparelli, Igor Diemberger, Giuseppe Boriani, Laura Adelaide Dalla Vecchia, Giuseppe Bellelli, Emanuele Marzetti, Gregory YH Lip, Matteo Cesari
Journal: Ageing Research Reviews (2022)
A randomized, multicenter, placebo-controlled, phase III study to evaluate the efficacy and safety of HER2/neu peptide GLSI-100 (GP2 + GM-CSF) in patients with residual disease or high-risk PCR after both neo-adjuvant and postoperative adjuvant anti-HER2 therapy, Flamingo-01.
Authors: Snehal Patel, Jaye Thompson, Mira Patel, F. Joseph Daugherty, C. Kent Osborne, Mothaffar F. Rimawi
Journal: Journal of Clinical Oncology (2022)

TPS1110 Background: GP2 is a biologic nine amino acid peptide of the HER2/ neu protein delivered in combination with Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) that stimulates an immune response targeting HER2/neu expressing cancers, the combination known as GLSI-100. In a prospective, randomized, single-blinded, placebo-controlled, multicenter Phase IIb study, no recurrences were observed in the HER2+ population after 5 years of follow-up, if the patient was treated with GLSI-100, survived and was followed from more than 6 months ( p = 0.0338). Immunotherapy elicited a potent response measured by skin tests and immunological assays. Of the 146 patients that have been treated with GLSI-100 over 4 clinical trials, GLSI-100 was well-tolerated and no serious adverse events were observed considered related to the immunotherapy. Methods: This Phase 3 trial is a prospective, randomized, double-blinded, multi-center study. After 1 year of trastuzumab-based therapy, 6 intradermal injections of GLSI-100 or placebo will be administered over the first 6 months and 5 subsequent boosters will be administered over the next 2.5 years for a total of 11 injections over 3 years. The participant duration of the trial will be 3 years treatment plus 1 additional year follow-up for a total of 4 years following the first year of treatment with trastuzumab-based therapy. Patients will be stratified based on residual disease status at surgery, hormone receptor status and region. Approximately 498 patients will be enrolled. To detect a hazard ratio of 0.3 in invasive breast cancer free survival (IBCFS), 28 events will be required. An interim analysis for superiority and futility will be conducted when at least 14 events have occurred. This sample size provides 80% power if the annual rate of events in placebo patients is 2.4% or greater. Up to 100 non-HLA-A*02 subjects will be enrolled in an open-label arm. Eligibility Criteria: The patient population is defined by these key eligibility criteria: HER2/neu positive and HLA-A*02; Residual disease or High risk pCR (Stage III at presentation) post neo-adjuvant therapy; Exclude Stage IV; Completed at least 90% of planned trastuzumab-based therapy. Trial Objectives: To determine if GP2 therapy increases IBCFS; To assess the safety profile of GP2; To monitor immunologic responses to treatment and assess relationship to efficacy and safety. Accrual: Site selection and study start-up is in progress at multiple sites. Target enrollment is 598 subjects. Clinical trial information: 05232916.
Prediction of 90-day mortality after radical cystectomy for bladder cancer in large-scale multicenter collaboration study
Authors: E. Laukhtina, E. Maier, V.M. Schuettfort, C. Lonati, F. Soria, S. Albisinni, W. Krajewski, G. Basile, G. Ploussard, J.Y. Teoh, B. Pradere, D. D`andrea, K. Mori, R. Sanchez Salas, M.C. Mir, C. Simeone, S. Zamboni, A. Mattei, R. Carando, M. Fisch, E. Xylinas, M. May, S.F. Shariat, M. Moschini, A. Aziz
Journal: European Urology (2022)
The impact of diabetes on the performance of skeletal muscle density (SMD) in screening for frailty: Findings from the Cancer and Aging Resilience Evaluation (CARE) Registry.
Authors: Sydney T Thai, Jennifer Leigh Lund, Charles Poole, Til Sturmer, Christian Harmon, Mustafa Al-Obaidi, Grant Richard Williams
Journal: Journal of Clinical Oncology (2022)

12037 Background: SMD is a marker of myosteatosis that can be obtained from routine computed tomography (CT) imaging and could be used to screen patients for further frailty evaluation. But diabetes (DM) is linked with myosteatosis in men and SMD utility for patients with DM is unknown. We assessed SMD performance as a frailty screening tool in older adults with primarily gastrointestinal cancer and compared performance in patients stratified by sex and DM. Methods: We analyzed CARE Registry patients at baseline, a sample with mostly late-stage, gastrointestinal malignancies. Frailty and DM were captured in the CARE tool, a patient-reported geriatric assessment. SMD was calculated from CT scans at L3 vertebrae. Analyses were run for each sex and by DM status. We used linear regression to assess crude associations of SMD and frailty score. SMD performance in classifying frail status (vs. non-frail) was analyzed with 1) area under the receiver operating characteristic curves (AUC) and confidence intervals (CIs); and 2) sensitivity and specificity for sex-specific SMD quartile cut-offs (Q1, median, Q3). Cut-off performance was compared between patients with DM vs. without using differences in sensitivity and specificity and CIs. CIs were estimated with 2,000 bootstrap replicates. Results: The analytic sample (N=874; 27% DM, 32% frail) was 39% female with median age 68 years. For each sex-DM subset, regression results had negative slopes indicating that low SMD was associated with higher frailty score. AUCs for women with and without DM were 0.57 (95% CI 0.45-0.69) and 0.62 (0.54-0.70). AUCs for men with and without DM were 0.68 (0.59-0.77) and 0.58 (0.52-0.65). Sex-stratified sensitivity and specificity results are below. Median cut-offs had both sensitivity and specificity &gt;0.50; Q3 cut-offs had higher sensitivity but low specificity. Conclusions: SMD could be used to pre-screen older adults with and without DM for further clinical frailty assessment. With high-sensitivity cut-offs (Q3), 13% to 26% of frail patients could be missed. Compared to other groups, SMD pre-screening for men with DM may miss the fewest frail patients but would produce many false-positives. [Table: see text]
A longitudinal study assessing the impact of ongoing COVID-19 pandemic among hematology-oncology trainees.
Authors: Sufana Shikdar, Rabia Saleem, Joel Alcid, Sarbajit Mukherjee, Ayesha Hassan, Vinay E. Keshava, Humza Razaq, Raid Aljumaily
Journal: Journal of Clinical Oncology (2022)

11033 Background: Hematology-Oncology (HO) trainees faced significant challenges due to the COVID-19 pandemic highlighted by a previous survey (Durani, Urshila, et al. "Impact of COVID-19 on Hematology-Oncology Trainees: A Quantitative and Qualitative Assessment." JCO Oncology Practice (2021): OP-21). Despite the positive impact of effective vaccines, the pandemic is still ongoing; thus, the challenges remain. Our aim is to evaluate how well the trainees have adapted to changes in their clinical training environment after the early phase of the COVID-19 pandemic. Methods: A cross-sectional internet-based survey (Shih, Grace, et al. "The impact of the COVID‐19 pandemic on the education and wellness of US Pediatric Anesthesiology Fellows." Pediatric Anesthesia 31.3 (2021): 268-274) from December 10, 2021, to January 10, 2022, was obtained from the trainees enrolled in Accreditation Council for Graduate Medical Education (ACGME)-accredited HO fellowship programs in the United States in their fourth (PGY4), fifth (PGY5), and sixth (PGY6) postgraduate year. Results: The survey was completed by 102 trainees. Demographics of the participants are reported in Table. Interestingly, 51% reported an impact of COVD-19 on their employment plans, primarily due to the inability to interview in person (24%, n=23). Trainees experienced several stressors due to the pandemic, including fear of getting sick from a patient (71%) or a coworker (66%). Approximately 27% (n=26) experienced mental health issues requiring additional care. Less than one-third of the trainees were concerned about clinical expertise and procedural skills. Trainees also felt that the change of conference to virtual format impacted their learning activities compared to in-person education (66%, n=64). Most trainees (52%, n=53) reported limited involvement in COVID-related research and journal club education. Most had access to socialization (59%, n=60), virtual office hours (70%, n=72), and telehealth visits (83%, n=85). Female trainees (18%) were more likely to seek mental health care than the male trainees (7.8%) (P=.02). Female trainees (33%) also reported facing more challenges in their employment plans compared to males (16%) (P=.003). Conclusions: Our study highlights the challenges experienced by hematology-oncology trainees with the ongoing COVID-19 pandemic and reveals the gender gap related to employment plans and seeking mental health care. [Table: see text]
ZFHX4 mutation as a novel predictive biomarker for immune checkpoint blockade in non-small cell lung cancer.
Authors: Peng Shen, Di Zeng, Zhenzi Lin, Pei Lin, Mingyang Luo, Lele Zhao, Huizi Chai, Lingli Huang, Mingzhe Xiao
Journal: Journal of Clinical Oncology (2022)

e20535 Background: ZFHX4 mutation as a novel predictive biomarker for immune checkpoint blockade in non-small cell lung cancer. Methods: 165 NSCLC patients treated with ICIs from independent public cohorts(Rizvi2015; Hellmann2018; Miao 2018) were included to assess immunotherapeutic predictive performance of ZFHX4 mutation. The genomic, mRNA profile and its corresponding survival data were retrieved from The Cancer Genome Atlas (TCGA) database for prognostic analysis. Results: In public cohorts 43 (26.06%) NSCLC patients harbored ZFHX4 mutations. Longer PFS was detected in NSCLC patients with ZFHX4 mutation (ZFHX4-mut) compared with those with wildtype ZFHX4 (ZFHX4-wt) (median PFS 22.1 months vs 4.2 months, HR 0.37; 95% CI 0.22 to 0.61; p &lt; 0.001). Higher ORR and DCR were also observed in patients with ZFHX4-mut compared with ZFHX4-wt (ORR: 62.8% vs 21.3%, p＜0.001; DCR: 86.0% vs 60.7%, p＜0.001, respectively). In the multivariable Cox proportional hazards regression model adjusted by PD- L1 expression and tumor mutational burden (TMB) and other confounding factors, ZFHX4-mut remained an independent predictor (HR 0.43; 95% CI 0.22 to 0.83; p = 0.01). ZFHX4-mut was associated with significantly higher TMB compared to ZFHX4-wt (P＜0.001). According to ZFHX4 status and TMB level, we stratified patients into four subgroups: ZFHX4mut-TMB high, ZFHX4mut-TMB low, ZFHX4wt-TMB high, and ZFHX4wt-TMB low. As expected, ZFHX4mut-TMB high patients achieved the longest PFS 23 months (HR 0.21 95% CI 0.10 to 0.43; p &lt; 0.01) among all groups. The combination of ZFHX4 mutation and TMB-H had a better predictive effect. Conclusions: Our results suggested that ZFHX4 mutation might be a potential predictor for ICIs therapy in NSCLC. Prospective studies to further understand the mechanism are warranted.
CRISPR Modeling and Correction of Cardiovascular Disease
Authors: Ning Liu, Eric N. Olson
Journal: Circulation Research (2022)

Cardiovascular disease remains the leading cause of morbidity and mortality in the developed world. In recent decades, extraordinary effort has been devoted to defining the molecular and pathophysiological characteristics of the diseased heart and vasculature. Mouse models have been especially powerful in illuminating the complex signaling pathways, genetic and epigenetic regulatory circuits, and multicellular interactions that underlie cardiovascular disease. The advent of CRISPR genome editing has ushered in a new era of cardiovascular research and possibilities for genetic correction of disease. Next-generation sequencing technologies have greatly accelerated the identification of disease-causing mutations, and advances in gene editing have enabled the rapid modeling of these mutations in mice and patient-derived induced pluripotent stem cells. The ability to correct the genetic drivers of cardiovascular disease through delivery of gene editing components in vivo, while still facing challenges, represents an exciting therapeutic frontier. In this review, we provide an overview of cardiovascular disease mechanisms and the potential applications of CRISPR genome editing for disease modeling and correction. We also discuss the extent to which mice can faithfully model cardiovascular disease and the opportunities and challenges that lie ahead.